Bone loss is a serious clinical problem that is most commonly diagnosed in post-menopausal woman, but that can occur in all populations at all ages. Marx (2004) Science 305:1420-1422 and Lotinun et al. (2012) Curr Mol Pharmacol 5:195-204. Diseases, such as cancer, diabetes, inflammatory bowel disease, as well as inflammatory diseases requiring steroid treatments, can suppress bone formation and lead to increased fracture risk. Fractures associated with bone loss are a leading cause of hospitalization, disability, and premature mortality in the elderly, affecting over 2 million Americans and leading to 500,000 hospitalizations and placing of 180,000 individuals into nursing homes every year. Dempster (2011) Am J Manag Care 17(Suppl 6):S164-S169 and Dawson-Hughes et al. (2012) Osteoporos Int 23:811-820. U.S. medical costs associated with osteoporotic fractures were nearly $17 billion in 2005 and are estimated to accumulate to over $474 billion in 20 years. Blume and Curtis (2011) Osteoporo Int 22:1835-1844. Beyond increasing fracture risk, the skeleton serves a broad array of physiologic functions, and thus bone loss may directly affect glucose and insulin metabolism, organ and vascular repair, as well as immune system function. Ferron et al. (2010) Cell 142:296-308; Clemens and Karsenty (2011) J Bone Miner Res 26:677-680; Cappariello et al. (2014) Arch Biochem Biophys 558:70-78; and Charles and Nakamura (2014) Curr Osteoporos Rep 12:1-8.
Because of the magnitude of the problem, biotechnology and pharmaceutical companies have searched for therapeutics that slow, stop, or reverse bone loss. Regrettably, only one class of approved agents restores bone mass, and all approved agents have important limitations and side effects that impact their efficacy and long-term administration. Thus, there remains an urgent need for novel therapeutics that are well tolerated and effectively stimulate bone formation to restore bone mass.